Excitotoxic neuronal injury via activation of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in a variety of neurodegenerative disorders, including human immunodeficiency virus (HIV)-associated neurocognitive disorders (IHAND). The broad objective of this proposal is to improve our understanding of signaling pathways that promote neuronal survival against HIV-induced neurotoxicity, thereby enhancing our ability to develop therapeutics for HAND and related neurodegenerative disorders. In vitro modeling of HIV-induced neurotoxicity demonstrates that activation of certain neuronal G-protein coupled receptors (GPCRs), such as chemokine receptors, can counteract excitotoxic neuronal injury through modulation of cell survival signaling pathways. The APJ receptor is a recently described GPCR that, like chemokine receptors, can serve as a co-receptor for HIV entry in certain cells. Furthermore, APJ and its ligand apelin are highly expressed in the central nervous system (CNS), suggesting that apelin/APJ signaling could play a central role in modulating CNS responses to HIV-induced neurotoxicity. Our preliminary investigations suggest that apelin release following inflammatory- and/or NMDAR-mediated neuronal activation counteracts HIV-induced neurotoxicity via activation of cell survival kinases. Based on these findings, we hypothesize that apelin, acting as a soluble neuropeptide through APJ, activates a novel, endogenous neuronal survival response that integrates several cell survival signaling pathways following inflammatory- and/or NMDAR-mediated neuronal activation during HIV infection. Therefore, in this proposal, we will determine the mechanism(s) of apelin-mediated neuroprotection. Specific Aim 1 will use ELISAs and an antibody-based microarray to define the cell survival signaling pathways modulated by apelin/APJ interactions. Specific Aim 2 will identify an apelin function blocking antibody and use ELISAs, PCR, and an immunofluorescent neurotoxicity assay to identify functional changes in apelin expression and release during HIV-induced neurotoxicity. Specific Aim 3 will use calcium imaging and Western blotting to identify potential roles for apelin in modulating NMDAR-mediated excitotoxic cell signaling. PUBLIC HEALTH RELEVANCE: Excitotoxic neuronal injury has been implicated in a variety of neurodegenerative disorders, including hypoxia/ischemia, epilepsy, Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, and HIV-associated neurocognitive disorders (HAND). By improving our understanding of signal transduction pathways that promote neuronal survival against HIV-induced toxicity, we hope to enhance our ability to develop therapeutics for HAND and related neurodegenerative disorders.